Acute-onset epilepsy triggered by fever mimicking FIRES (febrile infectionrelated

epilepsy syndrome): The role of protocadherin 19 (PCDH19) gene mutation

1. Nicola Specchio,
2. Lucia Fusco and
3. Federico Vigevano
Article first published online: 21 JUL 2011
DOI: 10.1111/j.1528-1167.2011.03193.x
Wiley Periodicals, Inc. 2011 International League Against Epilepsy
Issue

Epilepsia
Volume 52, Issue 11, pages e172e175, November 2011


Additional Information(Show All)
How to CiteAuthor InformationPublication History
SEARCH
Search Scope
In this issue

Search String
Advanced >
Saved Searches >
ARTICLE TOOLS
Get PDF (54K)
Save to My Profile
E-mail Link to this Article
Export Citation for this Article
Get Citation Alerts
Request Permissions
More Sharing ServicesShare|Share on citeulikeShare on facebookShare on deliciousShare on
www.mendeley.comShare on twitter
Abstract
Article
References
Cited By
Enhanced Article (HTML) Get PDF (54K)
Keywords:
FIRES;
PCDH19;
Acute onset epilepsy;
Febrile onset;
Encephalopathy

Summary
To report differences and similarities between febrile infectionrelated epilepsy syndrome (FIRES) and epilepsy in
female patients with protocadherin 19 (PCDH19) mutation. These are two recently described epileptic conditions
characterized by drug-resistant epilepsy and cognitive impairment. We report, as exemplification, one of our patients
with acute-onset epilepsy triggered by fever with clinical course resembling FIRES, but with a missense mutation
of PCDH19 gene. The clinical characteristics of this patient are similar to those reported for FIRES. We believe that
female patients with febrile acute-onset epilepsy resembling FIRES are potential PCDH19 mutation carriers.
Febrile infectionrelated epilepsy syndrome (FIRES) is a severe condition characterized by acute onset of status
epilepticus during a febrile illness and subsequent refractory epilepsy in patients with previous normal development
(van Baalen et al., 2010). Cognitive outcome is variable, but in most of cases, mental retardation and behavioral
disturbances become evident during the course of epilepsy. Etiology remains unknown. This condition has been
already described as idiopathic catastrophic epileptic encephalopathy presenting with acute-onset intractable status
(Baxter et al., 2003), devastating epileptic encephalopathy in school-aged children (DESC) (Mikaeloff et al., 2006),
acute encephalitis with refractory, repetitive partial seizures (AERRPS) (Sakuma et al., 2010), and childhood
refractory focal epilepsy following acute febrile encephalopathy (Specchio et al., 2010). Clinical, neurophysiologic,
imaging features, and treatment strategies have also been reported, based mainly on its possible pathogenetic
mechanisms (Nabbout et al., 2011). The hypothesis on its etiology ranges from immune-mediated (Specchio et al.,
2010) to inflammation-mediated mechanisms (Nabbout et al., 2011). Possible differential diagnosis has been made
with limbic encephalitis (Meyer et al., 1995) and Alpers disease (El Sabbagh et al., 2010).
Moreover, a similar acute onset, precipitated by a febrile illness, is observed in female patients affected by infantile-
onset epilepsy associated with mental retardation or behavioral disorders due to mutations of protocadherin 19
(PCDH19) gene located at Xq22 (Specchio et al., 2011), which determine a calcium-dependent cellcell adhesion
molecule dysfunction (Dibbens et al., 2008). The clinical boundary between the two conditions can be subtle and
each form can be mistaken for the other. Within nine published and unpublished PCDH19 patients (Marini et al.,
2010; Specchio et al., 2011) followed at Bambino Ges Childrens Hospital in Rome, three patients presented (with)
epilepsy onset during an acute febrile illness with repetitive seizures or status epilepticus, followed by chronic
epilepsy, resembling FIRES. We describe in detail one case to summarize the similarities and the differences
between FIRES and epilepsy due to PCDH19 gene mutation.

Case Report
This is a 10-year-old girl born at term after an uneventful pregnancy. Family history was unremarkable. At the age of
8 months during febrile rotavirus gastroenteritis she presented high frequency focal seizures that quickly evolved
toward status epilepticus. Seizure recording revealed both asynchronous bilateral temporal and parietal seizure
onset, characterized by left or right eye deviation, bilateral blinking, sometimes limbs automatisms, and evolving to
secondarily generalization. Subclinical ictal discharges were also recorded. Interictal electroencephalography (EEG)
showed asynchronous bilateral central and posterior slow waves, intermingled with rare posterior temporal
epileptiform abnormalities. Periodic lateralized epileptiform discharges (PLEDs) were also evident over the posterior
right hemisphere. This acute phase lasted for 20 days during which the patient presented as accompanying
symptoms fever, visual attention deficit, and soporous state. Brain magnetic resonance imaging (MRI) was normal
including diffusion weighted images sequences. Blood samples were obtained, and cerebrospinal fluid (CSF)
analyses were performed. Viral tests included herpes simplex virus (HSV) 1 and 2, rotavirus, enterovirus, varicella-
zoster virus (VZV), rubella, cytomegalovirus (CMV), parvovirus B19, toxoplasma, EpsteinBarr virus (EBV),
enterovirus, human herpesvirus 6 (HHV-6), and mumps. All virologic studies were performed using DNA polymerase
chain reaction (PCR) and were normal except for rotavirus positivity. Oligoclonal immunoglobulin (Ig)G bands (OBs),
checked with isoelectric focusing, were present. Blood examination, moreover, revealed high titers of antibodies to
2-glycoprotein and anticardiolipin. Metabolic examination including lactic acid, organic acid, and amino acids were
normal.
During the follow-up the patient continued to present focal seizures, sometimes evolving to secondary generalization.
Seizures recurred in clusters lasting several days every 35 months, and were characterized by screams, sometimes
fear expression of the face, psychomotor arrest, and motor automatisms (head and eye deviation followed by right or
left focal motor seizures were sometimes also reported). Interictal EEG showed bilateral asynchronous slow
abnormalities and spikes-and-wave complexes over parietal, temporal, and occipital areas. Ictal EEG showed left or
right frontal or temporal discharges characterized by rhythmic focal low voltage theta activity increasing in amplitude
and decreasing in frequency. The following antiepileptic medications were ineffective: carbamazepine, topiramate,
phenobarbital, valproate, levetiracetam, phenytoin, and clobazam. During clusters only intravenous continuous
infusion of midazolam was useful. She was also treated with intravenous immunoglobulin and methylprednisone with
inconstant results.
Soon after epilepsy onset cognitive and motor regression was noted. Serial cognitive evaluations during the first
3 years of life revealed a mental developmental index (MDI) of 68 at 9 months, <50 at 22 months, and remained
stable at 29 and 33 months, indicative of a moderate-severe mental retardation. She also presented a pervasive
developmental disorder (PDD) characterized by autistic features and language delay. At the age of
7 years PCDH19 sequencing disclosed the new de novo missense heterozygous c.1129G>C (p.Asp377His)
mutation. Partial data of this patient have been already reported (Marini et al., 2010, Patient 7).

Discussion
The clinical features of epilepsy onset and evolution in the patient described could be suggestive of FIRES. This is,
however, one of the possible phenotypes of PCDH19 presentation. Other two different phenotypes have been
described (Marini et al., 2010): The first is characterized by focal epilepsy and the second by epileptic
encephalopathy with Dravets syndromelike features. The FIRES-like clinical picture might be a third phenotype
of PCDH19 presentation. In our series a similar febrile acute onset of the disease was recognized in 30% of patients
(three of nine).
Similarities between the two conditions should be acknowledged. Febrile acute onset with repetitive high frequency
seizures is clearly reported in patients with FIRES (van Baalen et al., 2010), and also with PCDH19 mutations (Marini
et al., 2010; Specchio et al., 2011). In the acute phase, antiepileptic drugs (AEDs) are ineffective both in FIRES
and PCDH19 patients, whereas intravenous midazolam continuous infusion might be effective in PCDH19 patients. In
chronic phase, seizures tend to decrease spontaneously, despite the treatment. Neuroimaging is most of the time
normal in both conditions: In some patients, temporomesial or insular hyperintensity has been reported for FIRES, but
these data are inconstant (van Baalen et al., 2010). An encephalitic process is suspected in both conditions, despite
normal CSF examination, because of febrile onset, sometimes associated with soporous state and interictal EEG
slow waves.
Seizures semiology might be similar in the two conditions, but some differences should be acknowledged. In FIRES,
although mainly tonicclonic generalized seizures have been reported (van Baalen et al., 2010), focal seizures with
eye deviation and sometimes automatisms (Specchio et al., 2010), or chewing movements have also been described
(Nabbout et al., 2011). In PCDH19 patients, seizures are mainly focal with or without motor component, but a
generalized onset has been noted. On the other side myoclonic seizures have been observed inPCDH19 patients
(Marini et al., 2010) but not in FIRES. In both diseases seizures arise, independently from right and left hemispheres
and tend to appear isolated or in clusters.
The main differences between these two clinical conditions are: age at onset, ranging between 6 and 38 months
in PCDH19 patients and between early childhood and the second decade in FIRES patients. In FIRES, apparently a
male predominance is evident (van Baalen et al., 2010), whereas PCDH19 patients are all
female. Table 1 summarizes the clinical characteristics and differences between these two diseases. Regarding
cognitive and motor skills during the follow-up, FIRES has mostly a severe disease course with cognitive regression
and motor deficits, whereas autistic features seem to predominate in PCDH19 patients. Normal cognitive
development has also been reported inPCDH19 patients (Marini et al., 2010; Specchio et al., 2011). At onset, the
main clinical findings might overlap and some differences could indeed be evident during the follow-up.
Epilepsy with PCDH19mutation FIRES
1. ICU, Intensive care unit; SG, secondary generalization; SW, slow waves; AED, antiepileptic drug.
Age at onset 3 months to 3.5 years 315 years
Sex Restricted to female Male preponderance
Conditions that precede
onset
Viral illness sometimes Viral illness constant (respiratory infection)
Fever at onset Most of cases Always
Number of seizures at
onset
Repetitive/status epilepticus Repetitive/status epilepticus
Type of seizures Focal with SG Focal with SG
Requiring ICU admission
and intubation
Not constant Almost constant
Interictal EEG onset Bilateral SW, rare focal epileptiform abnormalities
Diffuse SW, multifocal of focal epileptiform
abnormalities
Ictal EEG onset
Diffuse or frontal and temporal focal discharges (both
hemispheres)
Mainly frontal and temporal discharges (both
hemispheres)
MRI onset Normal
Normal or increased T2 signal intensity in bilateral
temporomesial structures or insula
Treatment onset Benzodiazepine more effective (barbiturate induced coma rare) AED ineffective (barbiturate induced coma frequent)
Drug resistance follow-up
Frequent but prolonged seizure-free periods are reported in
some patients
Constant
Seizure frequency follow-
up
Variable (weekly/monthly/yearly) Cluster reported as main
feature
Variable (weekly/monthly) Cluster reported
Type of seizures follow-
up
Focal sometimes with SG, absences, myoclonia Focal sometimes with SG
Interictal EEG follow-up Normal, bilateral SW, rare epileptiform abnormalities Asynchronous bilateral SW and epileptiform
Epilepsy with PCDH19mutation FIRES
abnormalities (frontal, temporal, multifocal)
Cognitive outcome
Cognitive deficit, autistic features, behavioral disturbances,
normal cognitive outcome also reported
Severe cognitive deficits, behavioral disturbances
Table 1. Summary of clinical findings and diagnostic examinations in FIRES and PCDH19 patients